ABSTRACT: PURPOSE: To develop a clinical staging system based on the PIRO concept (Predisposition, Infection, RESPONSE and Organ dysfunction) for hospitalized patients with infection. METHODS: One year prospective cohort study of all hospitalized patients with infection (n?=?1035), admitted into a large tertiary care, university hospital. Variables associated with hospital mortality were selected using logistic regressions. Based on the regression coefficients, a score for each PIRO component was developed and a classification tree was used to stratify patients into four stages of increased risk of hospital mortality. The final clinical staging system was then validated using an independent cohort (n?=?186). RESULTS: Factors significantly associated with hospital mortality were • for Predisposition: age, sex, previous antibiotic therapy, chronic hepatic disease, chronic hematologic disease, cancer, atherosclerosis and a Karnofsky index<70; • for Insult/Infection: type of infection • for RESPONSE: abnormal temperature, tachypnea, hyperglycemia and severity of infection and • for Organ dysfunction: hypotension and SOFA score?1. The area under the ROC curve (CI95%) for the combined PIRO model as a predictor for mortality was 0.85 (0.82-0.88). Based on the scores for each of the PIRO components and on the cut-offs estimated from the classification tree, patients were stratified into four stages of increased mortality rates: stage I: ?5%, stage II: 6-20%, stage III: 21-50% and stage IV: >50%. Finally, this new clinical staging system was studied in a validation cohort, which provided similar results (0%, 9%, 31% and 67%, in each stage, respectively). CONCLUSIONS: Based on the PIRO concept, a new clinical staging system was developed for hospitalized patients with infection, allowing stratification into four stages of increased mortality, using the different scores obtained in Predisposition, RESPONSE, Infection and Organ dysfunction. The proposed system will likely help to define inclusion criteria in clinical trials as well as tailoring individual management plans for patients with infection.